Asymmetric reduction of ketones is a key transformation in the pharmaceutical industry for the preparation of enantiomerically pure alcohols, particularly those bearing heterocycles (see, e.g., The handbook of Homogeneous Hydrogenation (Eds.: J. G. De Vries, C. J. Elsevier), Willey-VCH, Weinheim, 2007; and C. Hedberg, in Modern Reduction Methods (Eds.: P. G. Andersson, I. J. Munslow), WILEY-VCH, Weinheim, 2008, pp. 109-134). Chiral RuCl2(diphosphine)(diamine) complexes pioneered by Noyori and co-workers catalyze highly efficient asymmetric hydrogenation of a wide array of ketones to afford the corresponding alcohols (see, e.g., T. Ohkuma et al., J. Am. Chem. Soc. 1995, 117, 2675-2676; H. Doucet et al., Angew. Chem. Int. Ed. 1998, 37, 1703-1707; and T. Ohkuma et al., J. Am. Chem. Soc. 1998, 120, 13529-13530). Despite the variety of catalysts described in the literature (see, e.g., K. Mikami et al., Angew. Chem. Int. Ed. 1999, 38, 495-497; M. J. Burk et al., Org. Lett. 2000, 2, 4173-4176; and J. Wu et al., Chem. Eur. J. 2003, 9, 2963-2968); very few ruthenium catalysts have been able to hydrogenate cyclic ketones such as 1-tetralones (see, e.g., T. Ohkuma et al., Org. Lett. 2004, 6, 2681-2683; and T. Touge et al., J. Am. Chem. Soc. 2011, 133, 14960-14963). Furthermore, examples of heteroaryl cyclic ketones hydrogenation are extremely rare. To our knowledge, the only reported asymmetric hydrogenation of a heteroaryl cyclic ketone utilized a Ru-BINAP complex with a 1,4-diamine derived from natural mannitol for the reduction of 4,5,6,7-tetrahydrofuran-4-one (see T. Ohkuma et al, Org. Lett. 2004, 6, 2681-2683).
In addition, only a few chiral catalysts have been reported to exhibit turnover numbers (TON, molar ratio of converted substrate to catalyst) over 100,000 with simple aryl methyl ketones, while most of the reported chiral catalysts have TON lower than 1000, making these catalytic systems unsuitable for industrial applications (see, e.g., K. Tsutsumi et al., Org. Proc. Res. Develop. 2009, 13, 625-628). In the synthesis of potential cholesterylester transfer protein (CETP) inhibitors, we needed to perform an asymmetric reduction of the advanced intermediate ketone of type 1 as such as depicted in Scheme 1.

The reduction of 1 was initially conducted with one equivalent of borane-diethylaniline and 15-20 mol % (1R,2S)-cis-1-amino-2-indanol to afford 84% yield of (S)-2 in 96:4 er on multi-kilogram scale. Though the reaction performed well on scale-up, a greener and more efficient catalytic method was desired.
Therefore, there is a need for a more efficient method for carrying out asymmetric hydrogenations such as that shown in Scheme 1.